Clinical studies have documented the frequent association between chronic immune activation and osteoporosis. However, research in this area has not yet been applied to HIV disease, which, arguably, represents the quintessential clinical example of prolonged chronic immune activation. In HIV disease, CD8 T cells are subject to chronic stimulation, ultimately leading to replicative senescence. In fact, more than 65% of the CD8 T cell subset in HIV-infected persons consists of cells with characteristics suggestive of replicative senescence. Osteoporotic fractures in the elderly are associated with the presence of high proportions of cells with markers of replicative senescence. Similarly, bone changes have been reported in persons infected with HIV, but the relative contribution of chronic T cell stimulation versus anti-retroviral therapy is unknown. The goal of the proposed research is to begin to dissect the mechanisms underlying these clinical non-causal correlations. The unique cell culture system that has led to earlier insights on the role of senescent CD8 T cells in immune deficits associated with HIV disease will be exploited to address the role of replicative senescence in bone homeostasis. The in vivo relevance of this culture system is supported by the numerous phenotypic and functional similarities between the end-stage senescent ceils that are arise in vitro, and certain types of CD8 T cells present in the elderly and in younger persons infected with HIV. The following are the specific aims of the proposed research: (1) To analyze the effects of senescent CD8 T cells on osteoclasts, the bone-resorbing cells. These experiments, using alloantigen-specific cell cultures established from healthy individuals, will also address the potential role of lipid oxidation products in the regulation of CD8 T cell/osteoclast activity. (2) To analyze the effects of CD8 T cell replicative senescence on osteoblastic differentiation and activity of osteoprogenitor cells. The cultures established in Aim 1 will be used for these experiments. The proposed developmental studies represent the initial stage in the exploration of the potential interaction of senescent CD8 T cells with the pathways of bone destruction and bone formation as a component of HIV disease pathogenesis. The significance of this research is further enhanced by the increased long-term survival of HIV-infected persons, a positive outcome, but one which will ultimately result in larger numbers of persons whose bones are already affected by the normal aging process.